[go: up one dir, main page]

WO1994026731A1 - Inhibiteurs de la cyclogenase - Google Patents

Inhibiteurs de la cyclogenase Download PDF

Info

Publication number
WO1994026731A1
WO1994026731A1 PCT/CA1994/000264 CA9400264W WO9426731A1 WO 1994026731 A1 WO1994026731 A1 WO 1994026731A1 CA 9400264 W CA9400264 W CA 9400264W WO 9426731 A1 WO9426731 A1 WO 9426731A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
hydrogen
oxadiazol
halo
diazinyl
Prior art date
Application number
PCT/CA1994/000264
Other languages
English (en)
Inventor
Jacques Yves Gauthier
Yves Leblanc
Petpiboon Prasit
Original Assignee
Merck Frosst Canada Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Frosst Canada Inc. filed Critical Merck Frosst Canada Inc.
Priority to CA002161789A priority Critical patent/CA2161789A1/fr
Priority to AU67184/94A priority patent/AU6718494A/en
Publication of WO1994026731A1 publication Critical patent/WO1994026731A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/18—Radicals substituted by singly bound hetero atoms other than halogen by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/42—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms
    • C07D333/44—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms attached in position 5

Definitions

  • This invention relates to compounds and pharmaceutical compositions for the treatment of cyclooxygenase mediated diseases and methods of treatment thereof.
  • Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase.
  • prostaglandin G/H synthase also known as cyclooxygenase.
  • cyclooxygenase- 2 the gene for an inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources.
  • cyclooxygenase-2 This enzyme is distinct from the cyclooxygenase- 1 which has now also been cloned, sequenced and characterized from sheep, murine and human sources.
  • the second form of cyclooxygenase, cyclooxygenase-2 is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors.
  • prostaglandins have physiological and pathological roles, we have concluded that the constitutive enzyme, cyclooxygenase- 1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow.
  • cyclooxygenase-2 is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines.
  • a selective inhibitor of cyclooxygenase-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug (NSACD), and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects.
  • NSACD non-steroidal antiinflammatory drug
  • such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin- sensitive asthmatic subjects.
  • the invention encompasses compounds of Formula I
  • the invention also encompasses pharmaceutical compositions for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described herein.
  • the invention also encompasses methods of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases comprising: administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I as disclosed herein.
  • the invention encompasses compounds of Formula I
  • Rl is selected from the group consisting of
  • R2 is selected from the group consisting of
  • heteroaryl is (1) a monocyclic aromatic ring of 5 atoms, containing one hetero atom which is S, O or N and optionally 1, 2, or 3 additional hetero atoms which are N, or (2) a monocyclic aromatic ring of 6 atoms, containing 1, 2, 3, or 4 hetero atoms which are N, and wherein the substitutents on the heteroaryl are selected from the group consisting of
  • R3 is selected from the group consisting of
  • R4 is selected from the group consisting of
  • alkyl is defined to include linear, branched, and cyclic structures, with Cl-6alkyl including including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Cl-6alkoxy is intended to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration.
  • lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
  • Cl-6alkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration.
  • lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc.
  • the propylthio group signifies -SCH2CH2CH3.
  • the invention encompasses compounds of Formula I
  • R4 is hydrogen
  • R2 is selected from the group consisting of (a) C3-6alkyl, (b) mono or di substituted phenyl, and
  • Exemplifying the invention are the compounds of Table 1 including: 3-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)thiophene, 2-Nitro-3-(4-fluorophenyl)-4-((4-methylsulfonyl)phenyl)thiophene,
  • the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above.
  • the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase-2 and for treating cyclooxygenase-2 mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above.
  • the invention encompasses a method of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases as disclosed herein comprising: administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I as disclosed herein.
  • the invention encompasses a method of inhibiting cyclooxygenase-2 and treating cyclooxygenase-2 mediated diseases as disclosed herein comprising: administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I as disclosed herein.
  • compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, mo holine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as argin
  • these diseases include pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries.
  • Compounds of Formula I are useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, following surgical and dental procedures.
  • such compounds may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer.
  • Compounds of Formula I will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma and Alzheimers disease.
  • compounds of Formula I will prove useful as alternatives to conventional non-steroidal anti-inflammatory drugs (NSAID'S) particularly where such non-steroidal anti-inflammatory drugs may be contra-indicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; Gl bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems; kidney disease; those prior to surgery or taking anticoagulants.
  • NSAID'S non-steroidal anti-inflammatory drugs
  • compositions for treating cyclooxygenase-2 mediated diseases as defined above comprising a non-toxic therapeutically effective amount of compound of Formula I as defined above and one or more ingredients such as another pain reliever including acetaminophen or phenacetin; a potentiator including caffeine; an H2- antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antitussive including codeine, hydrocodone, caramiphen, carbetapentane, or
  • the invention encompasses a method of treating cyclooxygenase mediated diseases comprising administration to a patient in need of such treatment a non-toxic therapeutically effective amount of compound of Formula I, optionally co-administered with one or more of such ingredients as listed immediately above.
  • Compounds of the present invention are inhibitors of cyclooxygenase-2 and are thereby useful in the treatment of cyclooxygenase-2 mediated diseases as enumerated above. This activity is illustrated by their ability to selectively inhibit cyclooxygenase-2 over cyclooxygenase- 1. Accordingly, in one assay, the ability of the compounds of this invention to treat cyclooxygenase mediated diseases can be demonstrated by measuring the amount of prostaglandin E2 (PGE2) synthesized in the presence of arachidonic acid, cyclooxygenase- 1 or cyclooxygenase-2 and a compound of Formula I.
  • PGE2 prostaglandin E2
  • the IC50 values represent the concentration of inhibitor required to return PGE2 synthesis to 50% of that obtained as compared to the uninhibited control. Illustrating this aspect, we have found that Compounds 1 through 25 are more than 100 times more effective in inhibiting COX-2 than they are at inhibiting COX-1. In addition they all have a COX-2 IC50 of 1 nM to 1 ⁇ M. By way of comparison, Ibuprofen has an IC50 for COX-2 of 1 ⁇ M, and Indomethacin has an IC50 for COX-2 of approximately 100 nM.
  • compounds of Formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • warm ⁇ blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc.
  • the compounds of the invention are effective in the treatment of humans.
  • pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined may optionally include one or more ingredients as listed above.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin,
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of Formula (I) are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • Dosage levels of the order of from about 0.01 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 gms per patient per day.
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 gms per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 gm of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the compounds of the present invention can be prepared by the general method described by J. Nakayama et al., Tetrahedron Lett., 26 (16), 1983-1984 (1985). Accordingly, intermediate III, obtained from the base catalyzed coupling of an ⁇ -mercaptoacetophenone and an ⁇ -haloacetophenone, is treated with titanium tetrachloride and zinc at low temperature in an inert solvent such as tetrahydrofuan to give an intermediate 3,4-dihydroxythiolane IV. This compound can then be dehydrated by heating it in a solvent such as toluene in the presence of an acid such as p-toluenesulfonic acid to yield II. This compound can be oxidized with a reagent such as the magnesium salt of mono- peroxyphtalic acid (MMPP) or m-chloroperoxybenzoic acid (mCPBA) to yield I.
  • MMPP mono- peroxyphtalic acid
  • mCPBA m-
  • I contains a substituent Rl which can be introduced by an aromatic electrophilic substitution
  • Rl substituent which can be introduced by an aromatic electrophilic substitution
  • this substituent can be introduced by treating V with a base such as n- BuLi at low temperature and quenching the anion with sulfur dioxide to give a lithium arylsulfinate intermediate. This intermediate can then be converted to an arylsulfonyl chloride which will react with NH3 to provide Id.
  • This general procedure has been described by T. Hameda and O. Yonemitsu, Synthesis, 852 (1986).
  • Table I illustrates compounds of Formula I, which are representative of the present invention. Representative biological data and the assays utilized to generate the data is provided immediately thereafter.
  • Human osteosarcoma 143.98.2 cells were cultured in DULBECCOS MODIFIED EAGLES MEDIUM (SIGMA) containing 3.7 g/1 NaHC03 (SIGMA), 100 ⁇ g/1 gentamicin (GIBCO), 25 mM HEPES, pH 7.4 (SIGMA), 100 IU/ml penicillin (FLOW LABS), 100 ⁇ g/ml streptomycin (FLOW LABS), 2 mM glutamine (FLOW LABS) and 10% fetal bovine serum (GIBCO). Cells were maintained at 37°C, 6% C02 in 150 cm2 tissue culture flasks (CORNING).
  • U-937 cells (ATCC CRL 1593) were cultured in 89% RPMI-1640 (SIGMA), 10% fetal bovine serum (GIBCO), containing 50 IU/ml penicillin (FLOW LABS), 50 ⁇ g/ml streptomycin (FLOW LABS) and 2 g/1 NaHC ⁇ 3 (SIGMA).
  • Cells were maintained at a density of OJ-2.0 x 106/ml in 1 liter spinner flasks (CORNING) at 37°C, 6% C02- For routine subculturing, cells were diluted in fresh medium and transferred to fresh flasks.
  • osteosarcoma 143.98.2 cells were cultured in 1 ml of media in 24-well multidishes (NUNCLON) until confluent. The number of cells per assay was determined from replicate plates prior to assays, using standard procedures. Immediately prior to cyclooxygenase assays, media was aspirated from cells, and the cells washed once with 2 ml of Hanks balanced salts solution (HBSS; SIGMA) prewarmed to 37°C. 1 ml of prewarmed HBSS was then added per well.
  • HBSS Hanks balanced salts solution
  • Osteosarcoma 143.98.2 and U-937 samples were neutralized by the addition of 100 ⁇ l of IN NaOH. Samples were then mixed by vortexing, and PGE2 levels measured using a PGE2 radio- immunoassay (NEW ENGLAND NUCLEAR-DUPONT) according to the manufacturers instructions. This procedure was automated using a BIOMEK 1000 (BECKMAN). Levels of PGE2 were calculated from the standard curve determined using BECKMAN IMMUNOFTT EIA/RIA analysis software. Results
  • MMMP magnesium monoperoxyphthalate
  • Optical Isomers - Diastereomers - Geometric Isomers Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
  • Step 1 4'-(MethylthioV2-chloroacetophenone
  • Step 3 4'-fMethylthio ' )phenacyl-4-fluorophenacyl sulfide
  • Step 4 3-(4-FluorophenylV4-f( -methylthio phenyDthiophene
  • Step 1 3-(4-FluorophenylV4-(4-bromophenyl)thiophene Following the procedures of Example 1, Steps 2-7, but replacing 4'-(methylthio)-2-chloroacetophenone by 4-bromophenyl bromide in Step 2, there was obtained the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de la formule (I) utilisable dans le traitement de maux à médiation cyclogénasique, tels que la douleur, la fièvre et les inflammations, liés à différents états dont les fièvres rhumatismales, les signes fonctionnels associés à la grippe ou à d'autres infections virales, aux refroidissements ordinaires, aux douleurs du bas du dos et de la nuque, à la dysménorrhée, aux maux de tête et de dents, aux entorses et foulures, à la myosite, aux neuralgie, aux synovites, à l'arthrite y compris l'arthrite rhumatoïde dégénérative des articulations (ostéoarthrite), à la goutte et à la spondylite ankylosante, à la bursite, aux brûlures, aux blessures et à la maladie d'Alzheimer. Dans la formule (I), R3 est sélectionné dans le groupe constitué par: (1) -S(O)¿2?CH3, (2) -S(O)(NH)CH3, (3) -S(O)NH2, et (4) -S(O)2NH2.
PCT/CA1994/000264 1993-05-13 1994-05-11 Inhibiteurs de la cyclogenase WO1994026731A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CA002161789A CA2161789A1 (fr) 1993-05-13 1994-05-11 Derives de substitution en 2 du 3,4-diarylthiofene, inhibiteurs de la cyclooxygenase
AU67184/94A AU6718494A (en) 1993-05-13 1994-05-11 2-substituted-3,4-diarylthiophene derivatives as inhibitors of cyclooxygenase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US061,354 1987-06-11
US6135493A 1993-05-13 1993-05-13

Publications (1)

Publication Number Publication Date
WO1994026731A1 true WO1994026731A1 (fr) 1994-11-24

Family

ID=22035257

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA1994/000264 WO1994026731A1 (fr) 1993-05-13 1994-05-11 Inhibiteurs de la cyclogenase

Country Status (3)

Country Link
AU (1) AU6718494A (fr)
CA (1) CA2161789A1 (fr)
WO (1) WO1994026731A1 (fr)

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006840A1 (fr) * 1994-08-29 1996-03-07 Merck Frosst Canada Inc. Heterocycles bicycliques diaryles utilises comme inhibiteurs de cyclooxygenase-2
WO1996011676A1 (fr) * 1994-10-12 1996-04-25 Merck Sharp & Dohme Limited Utilisation d'inhibiteurs de la cyclo-oxygenase dans le traitement de maladies neurodegeneratives
GB2294879A (en) * 1994-10-19 1996-05-15 Merck & Co Inc Cylcooxygenase-2 Inhibitors
WO1996038442A1 (fr) * 1995-06-02 1996-12-05 G.D. Searle & Co. Sulfonylphenylheterocycles substitues utilises comme inhibiteurs de cyclooxygenase-2 et de 5-lipoxygenase
WO1996041626A1 (fr) * 1995-06-12 1996-12-27 G.D. Searle & Co. Compositions comprenant un inhibiteur de cyclooxygenase-2 et un inhibiteur de 5-lipoxygenase
WO1996041645A1 (fr) * 1995-06-12 1996-12-27 G.D. Searle & Co. Traitement d'inflammations par une combinaison d'un inhibiteur de la cyclooxygenase-2 et d'un antagoniste du recepteur de leukotriene b¿4?
EP0679157B1 (fr) * 1993-01-15 1997-11-19 G.D. Searle & Co. Nouveaux thiophenes 3,4-diaryle et leurs analogues utilises comme agents anti-inflammatoires
WO1997045420A1 (fr) * 1996-05-31 1997-12-04 Merck & Co., Inc. Procede pour la fabrication d'heterocycles de phenyle utiles comme inhibiteurs de la cyclo-oxygenase-2 (cox-2)
US5700816A (en) * 1995-06-12 1997-12-23 Isakson; Peter C. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor
US5840746A (en) * 1993-06-24 1998-11-24 Merck Frosst Canada, Inc. Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases
US5883267A (en) * 1996-05-31 1999-03-16 Merck & Co., Inc. Process for making phenyl heterocycles useful as cox-2 inhibitors
US5932598A (en) * 1996-04-12 1999-08-03 G. D. Searle & Co. Prodrugs of benzenesulfonamide-containing COX-2 inhibitors
US6025353A (en) * 1997-11-19 2000-02-15 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents
US6045773A (en) * 1995-10-17 2000-04-04 G.D. Searle & Co. Method of detecting cyclooxygenase-2
US6172096B1 (en) 1996-02-13 2001-01-09 G. D. Searle & Co. Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a leukotriene B4 receptor antagonist
WO2001017996A1 (fr) * 1999-09-08 2001-03-15 Merck Frosst Canada & Co. Thiadiazoles-1,2,3, et leur utilisation comme inhibiteurs de cox-2
WO2001083475A1 (fr) * 2000-04-25 2001-11-08 J. Uriach & Cia S.A. Nouveaux composes heterocycliques a activite anti-inflammatoire
WO2002002547A1 (fr) * 2000-06-30 2002-01-10 Merck Frosst Canada & Co. Pyrones utilisées comme inhibiteurs de la cyclooxygénase-2
US6362209B1 (en) 1994-12-20 2002-03-26 Japan Tobacco Inc. Heterocyclic aromatic oxazole compounds and use thereof
WO2001081332A3 (fr) * 2000-04-25 2002-04-04 Pharmacia Corp Composes de 2-fluorobenzenesulfonyle utilises pour le traitement d'inflammations
US6376528B1 (en) 1996-02-13 2002-04-23 G. D. Searle & Co. Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor
US6407140B1 (en) 1996-02-13 2002-06-18 G.D. Searle & Co. Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor
US6432999B2 (en) 1995-06-02 2002-08-13 Pharmacia Corporation Pyrazole substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6512121B2 (en) 1998-09-14 2003-01-28 G.D. Searle & Co. Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6515014B2 (en) 1995-06-02 2003-02-04 G. D. Searle & Co. Thiophene substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
AU758566B2 (en) * 1997-10-31 2003-03-27 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in maintaining the fetal ductus ateriosus during treatment and prevention of preterm labor
US6613790B2 (en) 2001-04-17 2003-09-02 Pharmacia Corporation Prodrugs of COX-2 inhibitors
US6649645B1 (en) 1998-12-23 2003-11-18 Pharmacia Corporation Combination therapy of radiation and a COX-2 inhibitor for treatment of neoplasia
US6673818B2 (en) 2001-04-20 2004-01-06 Pharmacia Corporation Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation
US6716829B2 (en) 2000-07-27 2004-04-06 Pharmacia Corporation Aldosterone antagonist and cyclooxygenase-2 inhibitor combination therapy to prevent or treat inflammation-related cardiovascular disorders
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6858598B1 (en) 1998-12-23 2005-02-22 G. D. Searle & Co. Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6998415B2 (en) 1996-05-31 2006-02-14 Pharmacia Corporation Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US7067159B2 (en) 2003-12-05 2006-06-27 New Chapter, Inc. Methods for treating prostate cancer with herbal compositions
US7070816B2 (en) 2003-12-05 2006-07-04 New Chapter, Inc. Methods for treating prostatic intraepithelial neoplasia with herbal compositions
WO2007016677A2 (fr) 2005-08-02 2007-02-08 Nitromed, Inc. Composes antimicrobiens promoteurs d'oxyde nitrique, compositions et procedes d'utilisation
US7320996B2 (en) 2001-08-15 2008-01-22 Sugen, Inc Indolinone protein kinase inhibitors and cyclooxygenase inhibitors for use in combination therapy for the treatment of cancer
EP1977749A1 (fr) 1996-10-15 2008-10-08 G.D. Searle LLC Utilisation d' inhibiteurs de cyclooxygenase-2 dans le traitement et la prévention de la neoplasie
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
US7622142B2 (en) 2004-09-14 2009-11-24 New Chapter Inc. Methods for treating glioblastoma with herbal compositions
US7838023B2 (en) 2005-11-16 2010-11-23 Nitromed, Inc. Furoxan compounds, compositions and methods of use
US8067464B2 (en) 2004-10-04 2011-11-29 Nitromed, Inc. Compositions and methods using apocynin compounds and nitric oxide donors
US8067414B2 (en) 2006-03-29 2011-11-29 Nicox S.A. Nitric oxide enhancing prostaglandin compounds, compositions and methods of use
US8367038B2 (en) 2004-05-23 2013-02-05 HMI Medical Innovations, LLC Therameutin modulators
US8431110B2 (en) 2005-05-23 2013-04-30 Hmi Medical Innovations, Llc. Compounds and method of identifying, synthesizing, optimizing and profiling protein modulators
WO2016177776A1 (fr) 2015-05-04 2016-11-10 Academisch Medisch Centrum Biomarqueurs pour la détection de l'insensibilité à l'aspirine
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
CN107011320A (zh) * 2017-05-17 2017-08-04 广州医科大学 环丙基取代噻吩环烷胺类化合物及其应用
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
WO2022195579A1 (fr) 2021-03-15 2022-09-22 Saul Yedgar Dipalmitoyl-phosphatidyl-éthanol-amine conjuguée à l'acide hyaluronique en combinaison avec des médicaments anti-inflammatoires non stéroïdiens (ains) pour traiter ou soulager des maladies inflammatoires

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0087629A2 (fr) * 1982-03-03 1983-09-07 E.I. Du Pont De Nemours And Company 2,3-Diaryl-5-halo-thiophènes, anti-inflammatoires et/ou analgésiques
EP0365089A2 (fr) * 1988-10-18 1990-04-25 Merck & Co. Inc. 2-Aryl-5(3-méthoxy-5-(hydroxypropylsulphonyl)-4-propoxyphényl) tétrahydrothiophène et analogues
WO1994015932A1 (fr) * 1993-01-15 1994-07-21 G.D. Searle & Co. Nouveaux thiophenes 3,4-diaryle et leurs analogues utilises comme agents anti-inflammatoires

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0087629A2 (fr) * 1982-03-03 1983-09-07 E.I. Du Pont De Nemours And Company 2,3-Diaryl-5-halo-thiophènes, anti-inflammatoires et/ou analgésiques
EP0365089A2 (fr) * 1988-10-18 1990-04-25 Merck & Co. Inc. 2-Aryl-5(3-méthoxy-5-(hydroxypropylsulphonyl)-4-propoxyphényl) tétrahydrothiophène et analogues
WO1994015932A1 (fr) * 1993-01-15 1994-07-21 G.D. Searle & Co. Nouveaux thiophenes 3,4-diaryle et leurs analogues utilises comme agents anti-inflammatoires

Cited By (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0679157B1 (fr) * 1993-01-15 1997-11-19 G.D. Searle & Co. Nouveaux thiophenes 3,4-diaryle et leurs analogues utilises comme agents anti-inflammatoires
US5840746A (en) * 1993-06-24 1998-11-24 Merck Frosst Canada, Inc. Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases
US6329421B1 (en) 1994-08-29 2001-12-11 Merck Frosst Canada & Co. Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2
WO1996006840A1 (fr) * 1994-08-29 1996-03-07 Merck Frosst Canada Inc. Heterocycles bicycliques diaryles utilises comme inhibiteurs de cyclooxygenase-2
WO1996011676A1 (fr) * 1994-10-12 1996-04-25 Merck Sharp & Dohme Limited Utilisation d'inhibiteurs de la cyclo-oxygenase dans le traitement de maladies neurodegeneratives
GB2294879A (en) * 1994-10-19 1996-05-15 Merck & Co Inc Cylcooxygenase-2 Inhibitors
US5663195A (en) * 1994-10-19 1997-09-02 Merck & Co., Inc. Method of preventing bone loss
US6362209B1 (en) 1994-12-20 2002-03-26 Japan Tobacco Inc. Heterocyclic aromatic oxazole compounds and use thereof
US5643933A (en) * 1995-06-02 1997-07-01 G. D. Searle & Co. Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6515014B2 (en) 1995-06-02 2003-02-04 G. D. Searle & Co. Thiophene substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6753344B2 (en) 1995-06-02 2004-06-22 Pharmacia Corporation Thiophene substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6875785B2 (en) 1995-06-02 2005-04-05 Pharmacia Corporation Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6432999B2 (en) 1995-06-02 2002-08-13 Pharmacia Corporation Pyrazole substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6696477B2 (en) 1995-06-02 2004-02-24 Pharmacia Corporation Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
WO1996038442A1 (fr) * 1995-06-02 1996-12-05 G.D. Searle & Co. Sulfonylphenylheterocycles substitues utilises comme inhibiteurs de cyclooxygenase-2 et de 5-lipoxygenase
US5700816A (en) * 1995-06-12 1997-12-23 Isakson; Peter C. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor
WO1996041626A1 (fr) * 1995-06-12 1996-12-27 G.D. Searle & Co. Compositions comprenant un inhibiteur de cyclooxygenase-2 et un inhibiteur de 5-lipoxygenase
US6136839A (en) * 1995-06-12 2000-10-24 G. D. Searle & Co. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor
WO1996041645A1 (fr) * 1995-06-12 1996-12-27 G.D. Searle & Co. Traitement d'inflammations par une combinaison d'un inhibiteur de la cyclooxygenase-2 et d'un antagoniste du recepteur de leukotriene b¿4?
US6342510B1 (en) 1995-06-12 2002-01-29 G. D. Searle & Co. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitors and a leukotriene B4 receptor antagonist
US5990148A (en) * 1995-06-12 1999-11-23 G.D. Searle & Co. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor
US6045773A (en) * 1995-10-17 2000-04-04 G.D. Searle & Co. Method of detecting cyclooxygenase-2
US6376528B1 (en) 1996-02-13 2002-04-23 G. D. Searle & Co. Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor
US6172096B1 (en) 1996-02-13 2001-01-09 G. D. Searle & Co. Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a leukotriene B4 receptor antagonist
US7141599B2 (en) 1996-02-13 2006-11-28 Pharmacia Corporation Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor, a leukotriene B4 receptor inhibitor and a cyclosporin
US6407140B1 (en) 1996-02-13 2002-06-18 G.D. Searle & Co. Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor
US6617345B1 (en) 1996-02-13 2003-09-09 G.D. Searle & Co. Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor, a leukotriene B4 receptor inhibitor and a cyclosporin
LT4586B (lt) 1996-04-12 1999-12-27 G. D. Searle & Co. Pakeisti benzenesulfonamidų dariniai - ciklooksigenazės-2 inhibitorių provaistai
US7420061B2 (en) 1996-04-12 2008-09-02 Pharmacia Corporation Process for preparing prodrugs of benzenesulfonamide-containing COX-2 inhibitors
US5932598A (en) * 1996-04-12 1999-08-03 G. D. Searle & Co. Prodrugs of benzenesulfonamide-containing COX-2 inhibitors
US6815460B2 (en) 1996-04-12 2004-11-09 Pharmacia Corporation Process for preparing prodrugs of benzenesulfonamide-containing cox-2 inhibitors
US6436967B1 (en) 1996-04-12 2002-08-20 Pharmacia Corporation Process for preparing prodrugs of benzenesulfonamide-containing cox-2 inhibitors
WO1997045420A1 (fr) * 1996-05-31 1997-12-04 Merck & Co., Inc. Procede pour la fabrication d'heterocycles de phenyle utiles comme inhibiteurs de la cyclo-oxygenase-2 (cox-2)
US6998415B2 (en) 1996-05-31 2006-02-14 Pharmacia Corporation Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US5883267A (en) * 1996-05-31 1999-03-16 Merck & Co., Inc. Process for making phenyl heterocycles useful as cox-2 inhibitors
US6153787A (en) * 1996-05-31 2000-11-28 Merck & Co., Inc. Intermediates for making heterocycles useful as COX-2 inhibitors
EP1977749A1 (fr) 1996-10-15 2008-10-08 G.D. Searle LLC Utilisation d' inhibiteurs de cyclooxygenase-2 dans le traitement et la prévention de la neoplasie
AU758566B2 (en) * 1997-10-31 2003-03-27 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in maintaining the fetal ductus ateriosus during treatment and prevention of preterm labor
US6025353A (en) * 1997-11-19 2000-02-15 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents
US6512121B2 (en) 1998-09-14 2003-01-28 G.D. Searle & Co. Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6649645B1 (en) 1998-12-23 2003-11-18 Pharmacia Corporation Combination therapy of radiation and a COX-2 inhibitor for treatment of neoplasia
US6858598B1 (en) 1998-12-23 2005-02-22 G. D. Searle & Co. Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
WO2001017996A1 (fr) * 1999-09-08 2001-03-15 Merck Frosst Canada & Co. Thiadiazoles-1,2,3, et leur utilisation comme inhibiteurs de cox-2
WO2001083475A1 (fr) * 2000-04-25 2001-11-08 J. Uriach & Cia S.A. Nouveaux composes heterocycliques a activite anti-inflammatoire
ES2166710A1 (es) * 2000-04-25 2003-12-01 Uriach & Cia Sa J Nuevos compuestos heterociclicos con actividad antiinflamatoria.
WO2001081332A3 (fr) * 2000-04-25 2002-04-04 Pharmacia Corp Composes de 2-fluorobenzenesulfonyle utilises pour le traitement d'inflammations
US6465509B2 (en) 2000-06-30 2002-10-15 Merck Frosst Canada & Co. Pyrones as inhibitors of cyclooxygenase-2
WO2002002547A1 (fr) * 2000-06-30 2002-01-10 Merck Frosst Canada & Co. Pyrones utilisées comme inhibiteurs de la cyclooxygénase-2
US6716829B2 (en) 2000-07-27 2004-04-06 Pharmacia Corporation Aldosterone antagonist and cyclooxygenase-2 inhibitor combination therapy to prevent or treat inflammation-related cardiovascular disorders
US6613790B2 (en) 2001-04-17 2003-09-02 Pharmacia Corporation Prodrugs of COX-2 inhibitors
US6673818B2 (en) 2001-04-20 2004-01-06 Pharmacia Corporation Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation
US6699884B2 (en) 2001-04-20 2004-03-02 Pharmacia Corporation Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation
US7320996B2 (en) 2001-08-15 2008-01-22 Sugen, Inc Indolinone protein kinase inhibitors and cyclooxygenase inhibitors for use in combination therapy for the treatment of cancer
US7067159B2 (en) 2003-12-05 2006-06-27 New Chapter, Inc. Methods for treating prostate cancer with herbal compositions
US7070816B2 (en) 2003-12-05 2006-07-04 New Chapter, Inc. Methods for treating prostatic intraepithelial neoplasia with herbal compositions
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
US9795610B2 (en) 2004-05-23 2017-10-24 Gerard M. Housey Theramutein modulators
US11839617B2 (en) 2004-05-23 2023-12-12 HMI Medical Innovations, LLC Theramutein modulators
US10806738B2 (en) 2004-05-23 2020-10-20 HMI Medical Innovations, LLC Theramutein modulators
US11491164B2 (en) 2004-05-23 2022-11-08 HMI Medical Innovations, LLC Theramutein modulators
US8367038B2 (en) 2004-05-23 2013-02-05 HMI Medical Innovations, LLC Therameutin modulators
US10471065B2 (en) 2004-05-23 2019-11-12 HMI Medical Innovations, LLC Theramutein modulators
US11504377B2 (en) 2004-05-23 2022-11-22 HMI Medical Innovations, LLC Theramutein modulators
US12226420B2 (en) 2004-05-23 2025-02-18 HMI Medical Innovations, LLC Theramutein modultors
US11925647B2 (en) 2004-05-23 2024-03-12 HMI Medical Innovations, LLC Theramutein modulators
US9579326B2 (en) 2004-05-23 2017-02-28 HMI Medical Innovations, LLC Theramutein modulators
US7622142B2 (en) 2004-09-14 2009-11-24 New Chapter Inc. Methods for treating glioblastoma with herbal compositions
US8067464B2 (en) 2004-10-04 2011-11-29 Nitromed, Inc. Compositions and methods using apocynin compounds and nitric oxide donors
US8431110B2 (en) 2005-05-23 2013-04-30 Hmi Medical Innovations, Llc. Compounds and method of identifying, synthesizing, optimizing and profiling protein modulators
US11714080B2 (en) 2005-05-23 2023-08-01 HMI Medical Innovations, LLC Compounds and methods of identifying, synthesizing, optimizing and profiling protein modulators
US10955408B2 (en) 2005-05-23 2021-03-23 HMI Medical Innovations, LLC Compounds and methods of identifying, synthesizing, optimizing and profiling protein modulators
US10018619B2 (en) 2005-05-23 2018-07-10 HMI Medical Innovations, LLC Compounds and method of identifying, synthesizing, optimizing and profiling protein modulators
US11692998B2 (en) 2005-05-23 2023-07-04 HMI Medical Innovations, LLC Compounds and methods of identifying, synthesizing, optimizing and profiling protein modulators
US9222933B2 (en) 2005-05-23 2015-12-29 HMI Medical Innovations, LLC Compounds and method of identifying, synthesizing, optimizing and profiling protein modulators
US10473643B2 (en) 2005-05-23 2019-11-12 HMI Medical Innovations, LLC Compounds and methods of identifying, synthesizing, optimizing and profiling protein modulators
WO2007016677A2 (fr) 2005-08-02 2007-02-08 Nitromed, Inc. Composes antimicrobiens promoteurs d'oxyde nitrique, compositions et procedes d'utilisation
US7838023B2 (en) 2005-11-16 2010-11-23 Nitromed, Inc. Furoxan compounds, compositions and methods of use
US8846674B2 (en) 2006-03-29 2014-09-30 Nicox, S.A. Nitric oxide enhancing prostaglandin compounds, compositions and methods of use
US8067414B2 (en) 2006-03-29 2011-11-29 Nicox S.A. Nitric oxide enhancing prostaglandin compounds, compositions and methods of use
US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10792254B2 (en) 2013-12-17 2020-10-06 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
WO2016177776A1 (fr) 2015-05-04 2016-11-10 Academisch Medisch Centrum Biomarqueurs pour la détection de l'insensibilité à l'aspirine
CN107011320A (zh) * 2017-05-17 2017-08-04 广州医科大学 环丙基取代噻吩环烷胺类化合物及其应用
WO2022195579A1 (fr) 2021-03-15 2022-09-22 Saul Yedgar Dipalmitoyl-phosphatidyl-éthanol-amine conjuguée à l'acide hyaluronique en combinaison avec des médicaments anti-inflammatoires non stéroïdiens (ains) pour traiter ou soulager des maladies inflammatoires

Also Published As

Publication number Publication date
CA2161789A1 (fr) 1994-11-24
AU6718494A (en) 1994-12-12

Similar Documents

Publication Publication Date Title
WO1994026731A1 (fr) Inhibiteurs de la cyclogenase
AU689302B2 (en) Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2
EP0802917B1 (fr) Composes azotes aromatiques condenses 5,5-aryl-substitues utilises comme agents anti-inflammatoires
US5677318A (en) Diphenyl-1,2-3-thiadiazoles as anti-inflammatory agents
US5536752A (en) Phenyl heterocycles as COX-2 inhibitors
US5436265A (en) 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents
AU707773B2 (en) Diaryl-5-oxygenated-2-(5H)-furanones as COX-2 inhibitors
EP0799218B1 (fr) Diaryl-2-(5h)-furanones inhibiteurs de cox-2
US6222048B1 (en) Diaryl-2-(5H)-furanones as Cox-2 inhibitors
WO1994020480A1 (fr) Derives d'alcanesulfonamido-1-indanone utilises en tant qu'inhibiteurs de la cyclo-oxygenase
EP0739340A1 (fr) Heterocycles phenyliques utilises comme inhibiteurs de cox-2
AU2020397A (en) Bisarylcyclobutene derivates as cyclooxygenase inhibitors
CA2180624C (fr) Diphenyl-1,2,3-thiadiazoles, agents anti-inflammatoires
EP1181284B1 (fr) Oxydes de diphenyle-1,2,3-thiadiazole-3, compositions et procedes d'utilisation
HK1027470A (en) Phenyl heterocycles as cyclooxygenase-2 inhibitors
HK1033311A (en) Phenyl heterocycles as cyclooxygenase-2 inhibitors
WO2001017996A1 (fr) Thiadiazoles-1,2,3, et leur utilisation comme inhibiteurs de cox-2
HK1027344A (en) Phenyl heterocycles as cyclooxygenase-2 inhibitors
HK1027474B (en) Phenyl heterocycles as cyclooxygenase-2 inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR BY CA CN CZ FI HU JP KR KZ LK LV MG MN MW NO NZ PL RO RU SD SI SK TT UA US UZ

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 1995 537812

Country of ref document: US

Date of ref document: 19951024

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2161789

Country of ref document: CA

122 Ep: pct application non-entry in european phase
122 Ep: pct application non-entry in european phase